tbuckley/cabot-search huggingface dataset:
First Clinical Experience With [68Ga]Ga-FAPI-46-PET/CT Versus [18F]F-FDG PET/CT for Nodal Staging in Cervical Cancer
Authors: Simone Wegen, Katrin Sabine Roth, Jasmin Weindler, Karina Claus, Philipp Linde, Maike Trommer, Dennis Akuamoa-Boateng, Lutz van Heek, Christian Baues, Birgid Schömig-Markiefka, Klaus Schomäcker, Thomas Fischer, Alexander Drzezga, Carsten Kobe, Christhardt Köhler, Simone Marnitz
Journal: Clinical Nuclear Medicine (2023)

In several solid tumors, fibroblast activation protein (FAP) is overexpressed by cancer-associated fibroblasts in the tumor microenvironment. Preliminary evidence suggests that detection and staging are feasible with PET/CT imaging using [68Ga]-radiolabeled inhibitors of FAP also in cervical cancer (CC). Our study aims to explore the accuracy of [68Ga]Ga-fibroblast activation protein inhibitor (FAPI)-46 PET/CT and [18F]F-FDG PET/CT compared with histopathological results of surgical lymph node (LN) staging before primary chemoradiation.Seven consecutive women with treatment-naive and biopsy-proven locally advanced CC underwent both whole-body [68Ga]Ga-FAPI-46- and [18F]F-FDG PET/CT, for imaging nodal staging before systematic laparoscopic lymphadenectomy of the pelvic and para-aortic region. Location and number of suspicious LNs in PET imaging were recorded and compared with the results of histopathological analysis, including immunohistochemical staining for FAP.All 7 patients had focal uptake above background in their tumor lesions in [68Ga]Ga-FAPI-46 PET/CT. [68Ga]Ga-FAPI-46 PET/CT showed a higher tumor-to-background ratio (TBR) in primary tumor as well as in LN metastasis. Median TBRmax values using liver were 32.02 and 5.15 for [68Ga]Ga-FAPI-46 PET/CT and [18F]F-FDG PET/CT, respectively. Median TBRmax using blood pool was 18.45 versus 6.85 for [68Ga]Ga-FAPI-46 PET/CT and [18F]F-FDG PET/CT, respectively. Higher TBR also applies for nodal metastasis: TBRmax was 14.55 versus 1.39 (liver) and 7.97 versus 1.8 (blood pool) for [68Ga]Ga-FAPI-46 PET/CT and [18F]F-FDG PET/CT, respectively. Overall, [68Ga]Ga-FAPI-46 PET/CT detected more lesions compared with [18F]F-FDG PET/CT. Following surgical staging, a total of 5 metastatic LNs could be pathologically confirmed, of which 2 and 4 were positive by [18F]F-FDG PET/CT and [68Ga]Ga-FAPI-46 PET/CT, respectively.[68Ga]Ga-FAPI-46 PET/CT seems useful to improve detection of nodal metastasis in patients with CCs. Future studies should aim to compare [68Ga]Ga-FAPI-46 PET/CT to surgical staging of pelvic and para-aortic LNs in patients with locally advanced CC.
Genome-wide association study of brain biochemical phenotypes reveals distinct genetic architecture of Alzheimer’s disease related proteins
Authors: Stephanie R. Oatman, Joseph S. Reddy, Zachary Quicksall, Minerva M. Carrasquillo, Xue Wang, Chia-Chen Liu, Yu Yamazaki, Thuy T. Nguyen, Kimberly Malphrus, Michael Heckman, Kristi Biswas, Kwangsik Nho, Matthew Baker, Yuka A. Martens, Na Zhao, Jun Pyo Kim, Shannon L. Risacher, Rosa Rademakers, Andrew J. Saykin, Michael DeTure, Melissa E. Murray, Takahisa Kanekiyo, Dennis W. Dickson, Guojun Bu, Mariet Allen, Nilüfer Ertekin-Taner
Journal: Molecular Neurodegeneration (2023)

Abstract Background Alzheimer’s disease (AD) is neuropathologically characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. The main protein components of these hallmarks include Aβ40, Aβ42, tau, phosphor-tau, and APOE. We hypothesize that genetic variants influence the levels and solubility of these AD-related proteins in the brain; identifying these may provide key insights into disease pathogenesis. Methods Genome-wide genotypes were collected from 441 AD cases, imputed to the haplotype reference consortium (HRC) panel, and filtered for quality and frequency. Temporal cortex levels of five AD-related proteins from three fractions, buffer-soluble (TBS), detergent-soluble (Triton-X = TX), and insoluble (Formic acid = FA), were available for these same individuals. Variants were tested for association with each quantitative biochemical measure using linear regression, and GSA-SNP2 was used to identify enriched Gene Ontology (GO) terms. Implicated variants and genes were further assessed for association with other relevant variables. Results We identified genome-wide significant associations at seven novel loci and the APOE locus. Genes and variants at these loci also associate with multiple AD-related measures, regulate gene expression, have cell-type specific enrichment, and roles in brain health and other neuropsychiatric diseases. Pathway analysis identified significant enrichment of shared and distinct biological pathways. Conclusions Although all biochemical measures tested reflect proteins core to AD pathology, our results strongly suggest that each have unique genetic architecture and biological pathways that influence their specific biochemical states in the brain. Our novel approach of deep brain biochemical endophenotype GWAS has implications for pathophysiology of proteostasis in AD that can guide therapeutic discovery efforts focused on these proteins.
A phase 2 clinical trial of combined BRAF/MEK inhibition for <i>BRAF</i>V600E-mutated multiple myeloma
Authors: Nicola Giesen, Manik Chatterjee, Christof Scheid, Alexandra M. Poos, Britta Besemer, Kaya Miah, Axel Benner, Nicole Becker, Thomas Moehler, Ivana Metzler, Cyrus Khandanpour, Andrea Seidel-Glaetzer, Karolin Trautmann-Grill, K. Martin Kortüm, Carsten Müller-Tidow, Gunhild Mechtersheimer, Benjamin Goeppert, Albrecht Stenzinger, Niels Weinhold, Hartmut Goldschmidt, Katja Weisel, Marc S. Raab
Journal: Blood (2023)
The intracellular fate and transport mechanism of shape, size and rigidity varied nanocarriers for understanding their oral delivery efficiency
Authors: Xin Li, Seid Mahdi Jafari, Feibai Zhou, Hui Hong, Xin Jia, Xiaohong Mei, Guohua Hou, Yu Yuan, Bin Liu, Shanan Chen, Yifu Gong, Huiling Yan, Ruxin Chang, Jiayin Zhang, Fazheng Ren, Yuan Li
Journal: Biomaterials (2023)
Correction: Immunogenicity and reactogenicity of SARS-CoV-2 vaccines in people living with HIV in the Netherlands: A nationwide prospective cohort study
Authors: Kathryn S. Hensley, Marlou J. Jongkees, Daryl Geers, Corine H. GeurtsvanKessel, Yvonne M. Mueller, Virgil A. S. H. Dalm, Grigorios Papageorgiou, Hanka Steggink, Alicja Gorska, Susanne Bogers, Jan G. den Hollander, Wouter F. W. Bierman, Luc B. S. Gelinck, Emile F. Schippers, Heidi S. M. Ammerlaan, Marc van der Valk, Marit G. A. van Vonderen, Corine E. Delsing, Elisabeth H. Gisolf, Anke H. W. Bruns, Fanny N. Lauw, Marvin A. H. Berrevoets, Kim C. E. Sigaloff, Robert Soetekouw, Judith Branger, Quirijn de Mast, Adriana J. J. Lammers, Selwyn H. Lowe, Rory D. de Vries, Peter D. Katsikis, Bart J. A. Rijnders, Kees Brinkman, Anna H. E. Roukens, Casper Rokx
Journal: PLoS Medicine (2023)

Fig 3 panel B contains a mislabeled axis.The label 'Pre-
Football-specific extension of the IOC consensus statement: methods for recording and reporting of epidemiological data on injury and illness in sport 2020
Authors: Markus Waldén, Margo Mountjoy, Alan McCall, Andreas Serner, Andrew Massey, Johannes L Tol, Roald Bahr, Michel D'Hooghe, Natália Bittencourt, Francesco Della Villa, Michiko Dohi, Gregory Dupont, Mark Fulcher, Dina Christina (Christa) Janse van Rensburg, Donna Lu, Thor Einar Andersen
Journal: British Journal of Sports Medicine (2023)

Several sports have published consensus statements on methods and reporting of epidemiological studies concerning injuries and illnesses with football (soccer) producing one of the first guidelines. This football-specific consensus statement was published in 2006 and required an update to align with scientific developments in the field. The International Olympic Committee (IOC) recently released a sports-generic consensus statement outlining methods for recording and reporting epidemiological data on injury and illness in sport and encouraged the development of sport-specific extensions.The Fédération Internationale de Football Association Medical Scientific Advisory Board established a panel of 16 football medicine and/or science experts, two players and one coach. With a foundation in the IOC consensus statement, the panel performed literature reviews on each included subtopic and performed two rounds of voting prior to and during a 2-day consensus meeting. The panel agreed on 40 of 75 pre-meeting and 21 of 44 meeting voting statements, respectively. The methodology and definitions presented in this comprehensive football-specific extension should ensure more consistent study designs, data collection procedures and use of nomenclature in future epidemiological studies of football injuries and illnesses regardless of setting. It should facilitate comparisons across studies and pooling of data.
Predisposing and Precipitating Factors Associated With Delirium
Authors: Cora H. Ormseth, Sara C. LaHue, Mark A. Oldham, S. Andrew Josephson, Evans Whitaker, Vanja C. Douglas
Journal: JAMA Network Open (2023)

Despite discrete etiologies leading to delirium, it is treated as a common end point in hospital and in clinical trials, and delirium research may be hampered by the attempt to treat all instances of delirium similarly, leaving delirium management as an unmet need. An individualized approach based on unique patterns of delirium pathophysiology, as reflected in predisposing factors and precipitants, may be necessary, but there exists no accepted method of grouping delirium into distinct etiologic subgroups.To conduct a systematic review to identify potential predisposing and precipitating factors associated with delirium in adult patients agnostic to setting.A literature search was performed of PubMed, Embase, Web of Science, and PsycINFO from database inception to December 2021 using search Medical Subject Headings (MeSH) terms consciousness disorders, confusion, causality, and disease susceptibility, with constraints of cohort or case-control studies. Two reviewers selected studies that met the following criteria for inclusion: published in English, prospective cohort or case-control study, at least 50 participants, delirium assessment in person by a physician or trained research personnel using a reference standard, and results including a multivariable model to identify independent factors associated with delirium.A total of 315 studies were included with a mean (SD) Newcastle-Ottawa Scale score of 8.3 (0.8) out of 9. Across 101 144 patients (50 006 [50.0%] male and 49 766 [49.1%] female patients) represented (24 015 with delirium), studies reported 33 predisposing and 112 precipitating factors associated with delirium. There was a diversity of factors associated with delirium, with substantial physiological heterogeneity.In this systematic review, a comprehensive list of potential predisposing and precipitating factors associated with delirium was found across all clinical settings. These findings may be used to inform more precise study of delirium's heterogeneous pathophysiology and treatment.
Targeted long-read sequencing captures CRISPR editing and AAV integration outcomes in brain
Authors: Bryan P. Simpson, Carolyn M. Yrigollen, Aleksandar Izda, Beverly L. Davidson
Journal: Molecular Therapy (2023)

Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing is an emerging therapeutic modality that shows promise in Huntington's disease and spinocerebellar ataxia (SCA) mouse models. However, advancing CRISPR-based therapies requires methods to fully define in vivo editing outcomes. Here, we use polymerase-free, targeted long-read nanopore sequencing and evaluate single- and dual-gRNA AAV-CRISPR editing of human ATXN2 in transgenic mouse models of SCA type 2 (SCA2). Unbiased high sequencing coverage showed 10%-25% editing. Along with intended edits there was AAV integration, 1%-2% of which contained the entire AAV genome and were largely unmethylated. More than 150 kb deletions at target loci and rearrangements of the transgenic allele (1%) were also found. In contrast, PCR-based nanopore sequencing showed bias for partial AAV fragments and inverted terminal repeats (ITRs) and failed to detect full-length AAV. Cumulatively this work defines the spectrum of outcomes of CRISPR editing in mouse brain after AAV gene transfer using an unbiased long-read sequencing approach.
History of Incarceration and Its Association With Geriatric and Chronic Health Outcomes in Older Adulthood
Authors: Ilana R. Garcia-Grossman, Irena Cenzer, Michael A. Steinman, Brie A. Williams
Journal: JAMA Network Open (2023)

Although incarcerated older adults experience higher rates of chronic disease and geriatric syndromes, it is unknown whether community-dwelling older adults with a history of incarceration are also at risk for worse health outcomes.To evaluate the association between a history of incarceration and health outcomes, including chronic health conditions and geriatric syndromes, in older age.This cross-sectional study using population-based data from the nationally representative Health and Retirement Study included US community-dwelling adults aged 50 years or older who completed the 2012 or 2014 survey waves assessing self-reported history of incarceration. Statistical analysis was completed from December 2021 to July 2022.Self-reported history of incarceration.Geriatric health outcomes included cognitive impairment, mobility impairment, vision impairment, hearing impairment, urinary incontinence, and impairment of activities of daily living (ADLs). Chronic health outcomes included high blood pressure, diabetes, chronic lung disease, heart disease, stroke, mental health conditions, heavy alcohol use, and self-reported health. Survey weights were applied to adjust for the survey design.Among 13 462 participants, 946 (7.6%) had experienced incarceration (mean [SD] age, 62.4 [7.8] years); compared with 12 516 people with no prior incarceration (mean [SD] age, 66.7 [10.0] years), previously incarcerated adults were more likely to be male (83.0% vs 42.8%; P < .001) and in the lowest quartile of wealth (44.1% vs 21.4%; overall P < .001). After adjusting for age, sex, race and ethnicity, wealth, educational attainment, and uninsured status, a history of incarceration was associated with a 20% to 80% increased risk of all geriatric syndromes evaluated, including impairment of ADLs (relative risk [RR], 1.62; 95% CI, 1.40-1.88) and hearing impairment (RR, 1.22; 95% CI, 1.04-1.44). Incarceration was also associated with increased risk of some chronic diseases, including chronic lung disease (RR, 1.56; 95% CI, 1.27-1.91), mental health conditions (RR, 1.80; 95% CI, 1.55-2.08), and heavy alcohol use (RR, 2.13; 95% CI, 1.59-2.84). Prior incarceration was not associated with diabetes or cardiovascular conditions.In this study, at least 1 in 15 older US adults reported a history of incarceration in their lifetime. Past incarceration was associated with many chronic diseases and geriatric syndromes even after accounting for socioeconomic status. These findings suggest that attention to incarceration history may be an important consideration in understanding and mitigating health risks in older age.
STING agonism overcomes STAT3-mediated immunosuppression and adaptive resistance to PARP inhibition in ovarian cancer
Authors: Liya Ding, Qiwei Wang, Antons Martincuks, Michael J Kearns, Tao Jiang, Ziying Lin, Xin Cheng, Changli Qian, Shaozhen Xie, Hye-Jung Kim, Inga-Maria Launonen, Anniina Färkkilä, Thomas M Roberts, Gordon J Freeman, Joyce F Liu, Panagiotis A Konstantinopoulos, Ursula Matulonis, Hua Yu, Jean J Zhao
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Poly (ADP-ribose) polymerase (PARP) inhibition (PARPi) has demonstrated potent therapeutic efficacy in patients with BRCA-mutant ovarian cancer. However, acquired resistance to PARPi remains a major challenge in the clinic. Methods PARPi-resistant ovarian cancer mouse models were generated by long-term treatment of olaparib in syngeneic Brca1-deficient ovarian tumors. Signal transducer and activator of transcription 3 (STAT3)-mediated immunosuppression was investigated in vitro by co-culture experiments and in vivo by analysis of immune cells in the tumor microenvironment (TME) of human and mouse PARPi-resistant tumors. Whole genome transcriptome analysis was performed to assess the antitumor immunomodulatory effect of STING (stimulator of interferon genes) agonists on myeloid cells in the TME of PARPi-resistant ovarian tumors. A STING agonist was used to overcome STAT3-mediated immunosuppression and acquired PARPi resistance in syngeneic and patient-derived xenografts models of ovarian cancer. Results In this study, we uncover an adaptive resistance mechanism to PARP inhibition mediated by tumor-associated macrophages (TAMs) in the TME. Markedly increased populations of protumor macrophages are found in BRCA-deficient ovarian tumors that rendered resistance to PARPi in both murine models and patients. Mechanistically, PARP inhibition elevates the STAT3 signaling pathway in tumor cells, which in turn promotes protumor polarization of TAMs. STAT3 ablation in tumor cells mitigates polarization of protumor macrophages and increases tumor-infiltrating T cells on PARP inhibition. These findings are corroborated in patient-derived, PARPi-resistant BRCA1-mutant ovarian tumors. Importantly, STING agonists reshape the immunosuppressive TME by reprogramming myeloid cells and overcome the TME-dependent adaptive resistance to PARPi in ovarian cancer. This effect is further enhanced by addition of the programmed cell death protein-1 blockade. Conclusions We elucidate an adaptive immunosuppression mechanism rendering resistance to PARPi in BRCA1-mutant ovarian tumors. This is mediated by enrichment of protumor TAMs propelled by PARPi-induced STAT3 activation in tumor cells. We also provide a new strategy to reshape the immunosuppressive TME with STING agonists and overcome PARPi resistance in ovarian cancer.
Effect of Prescriber Notifications of Patient’s Fatal Overdose on Opioid Prescribing at 4 to 12 Months
Authors: Jason N. Doctor, Emily Stewart, Roneet Lev, Jonathan Lucas, Tara Knight, Andy Nguyen, Michael Menchine
Journal: JAMA Network Open (2023)

This randomized clinical trial evaluates the effect of prescriber notifications of a patient’s fatal overdose on opioid prescribing, including decreases in morphine milligram equivalents, new patients taking opioids, and patients taking a high dose, at 4 to 12 months after notification.
Severe COVID-19 Infection in Type 1 and Type 2 Diabetes During the First Three Waves in Sweden
Authors: Jon Edqvist, Christina Lundberg, Karin Andreasson, Lena Björck, Pigi Dikaiou, Johnny Ludvigsson, Marcus Lind, Martin Adiels, Annika Rosengren
Journal: Diabetes Care (2023)

OBJECTIVE Type 2 diabetes is an established risk factor for hospitalization and death in COVID-19 infection, while findings with respect to type 1 diabetes have been diverging. RESEARCH DESIGN AND METHODS Using nationwide health registries, we identified all patients aged ≥18 years with type 1 and type 2 diabetes in Sweden. Odds ratios (ORs) describe the general and age-specific risk of being hospitalized, need for intensive care, or dying, adjusted for age, socioeconomic factors, and coexisting conditions, compared with individuals without diabetes. Machine learning models were used to find predictors of outcomes among individuals with diabetes positive for COVID-19. RESULTS Until 30 June 2021, we identified 365 (0.71%) and 11,684 (2.31%) hospitalizations in 51,402 and 504,337 patients with type 1 and 2 diabetes, respectively, with 67 (0.13%) and 2,848 (0.56%) requiring intensive care unit (ICU) care and 68 (0.13%) and 4,020 (0.80%) dying (vs 7,824,181 individuals without diabetes [41,810 hospitalizations (0.53%), 8,753 (0.11%) needing ICU care, and 10,160 (0.13%) deaths). Although those with type 1 diabetes had moderately raised odds of being hospitalized (multiple-adjusted OR 1.38 [95% CI 1.24–1.53]), there was no independent effect on ICU care or death (OR of 1.21 [95% CI 0.94–1.52] and 1.13 [95% CI 0.88–1.48], respectively). Age and socioeconomic factors were the dominating features for predicting hospitalization and death in both types of diabetes. CONCLUSIONS Type 2 diabetes was associated with increased odds for all outcomes, whereas patients with type 1 diabetes had moderately increased odds of hospitalization but not ICU care and death.
Intranasal fentanyl and discharge from the emergency department among children with sickle cell disease and vaso‐occlusive pain: A multicenter pediatric emergency medicine perspective
Authors: Chris A. Rees, David C. Brousseau, Fahd A. Ahmad, Jonathan Bennett, Seema Bhatt, Amanda Bogie, Kathleen M. Brown, T. Charles Casper, Laura L. Chapman, Corrie E. Chumpitazi, Daniel M. Cohen, Carlton Dampier, Angela M. Ellison, Hartmut Grasemann, Dunia Hatabah, Robert W. Hickey, Lewis L. Hsu, Nitya Bakshi, Sara Leibovich, Prabhumallikarjun Patil, Elizabeth C. Powell, Rachel Richards, Syana Sarnaik, Debra L. Weiner, Claudia R. Morris
Journal: American Journal of Hematology (2023)

Children with sickle cell disease (SCD) commonly experience vaso-occlusive pain episodes (VOE) due to sickling of erythrocytes, which often requires care in the emergency department. Our objective was to assess the use and impact of intranasal fentanyl for the treatment of children with SCD-VOE on discharge from the emergency department in a multicenter study. We conducted a cross-sectional study at 20 academic pediatric emergency departments in the United States and Canada. We used logistic regression to test bivariable and multivariable associations between the outcome of discharge from the emergency department and candidate variables theoretically associated with discharge. The study included 400 patients; 215 (54%) were female. The median age was 14.6 (interquartile range 9.8, 17.6) years. Nineteen percent (n = 75) received intranasal fentanyl in the emergency department. Children who received intranasal fentanyl had nearly nine-fold greater adjusted odds of discharge from the emergency department compared to those who did not (adjusted odds ratio 8.99, 95% CI 2.81–30.56, p < .001). The rapid onset of action and ease of delivery without intravenous access offered by intranasal fentanyl make it a feasible initial parenteral analgesic in the treatment of children with SCD presenting with VOE in the acute-care setting. Further study is needed to determine potential causality of the association between intranasal fentanyl and discharge from the emergency department observed in this multicenter study.